title: Multifunctional tacrine-flavonoid hybrids with cholinergic, β-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer's disease.
abstract: A new series of tacrine-flavonoid hybrids (13a-u) had been designed, synthesized, and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of the molecules exhibited a significant ability to inhibit ChE and self-induced amyloid-β (Aβ₁₋₄₂) aggregation. Kinetic and molecular modeling studies also indicated compounds were mixed-type inhibitors, binding simultaneously to active, peripheral and mid-gorge sites of AChE. Particularly, compound 13k was found to be highly potent and showed a balanced inhibitory profile against ChE and self-induced Aβ₁₋₄₂ aggregation. Moreover, it also showed excellent metal chelating property and low cell toxicity. These results suggested that 13k might be an excellent multifunctional agent for AD treatment.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors.forename: Su-Yi
authors.initials: SY
authors.lastname: Li
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Wang
authors.forename: Sai-Sai
authors.initials: SS
authors.lastname: Xie
authors.forename: Neng
authors.initials: N
authors.lastname: Jiang
authors.forename: Kelvin D G
authors.initials: KD
authors.lastname: Wang
authors.forename: He-Quan
authors.initials: HQ
authors.lastname: Yao
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Sun
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Kong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000737:chemistry; D016166:Free Radical Scavengers / Q000737:chemistry; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010851:Picrates / Q000737:chemistry; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001713:Biphenyl Compounds; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D005419:Flavonoids; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D010446:Peptide Fragments; D010851:Picrates; C075222:amyloid beta-protein (1-42); D013619:Tacrine; C004931:1,1-diphenyl-2-picrylhydrazyl; D002802:Cholinesterases
keywords: ASNDIIUXKSSGTR-UHFFFAOYSA-N; Alzheimer's disease; CCSIEQWILAQNOJ-UHFFFAOYSA-N; CFTXWMALZMFVFR-UHFFFAOYSA-N; Cholinesterase; DAQOTHBGIZARGM-UHFFFAOYSA-N; DDOHQRNJXWAFAL-UHFFFAOYSA-N; FYFPJPCNMIMCSI-UHFFFAOYSA-N; Flavonoid; JBVVLTRVHVGZEU-UHFFFAOYSA-N; JBXYRSPJNIZSAT-UHFFFAOYSA-N; JFGPPVAZTXRZDC-UHFFFAOYSA-N; JWCIYSMFMZTUME-UHFFFAOYSA-N; LESFBJPJZADQHL-UHFFFAOYSA-N; MDVLYACOLMKYAL-UHFFFAOYSA-N; Metal chelator; NHRHUIFWROFHGI-UHFFFAOYSA-N; NYSKQVVKHYVKTB-UHFFFAOYSA-N; OXTPOGAMUKLJIJ-UHFFFAOYSA-N; PDCBHYYTMYMYBE-UHFFFAOYSA-N; PGHRDQIVQWNEGD-UHFFFAOYSA-N; RQWXJZZQVBAPHB-UHFFFAOYSA-N; SXDGSJQISGFVLK-UHFFFAOYSA-N; TZWXGPOBAFCOHW-UHFFFAOYSA-N; Tacrine; VBAJECZQEAYMJO-UHFFFAOYSA-N; β-Amyloid aggregation